Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue
Prashanth Vallabhajosyula, … , Michael R. Rickels, Ali Naji
Prashanth Vallabhajosyula, … , Michael R. Rickels, Ali Naji
Published March 20, 2017
Citation Information: J Clin Invest. 2017;127(4):1375-1391. https://doi.org/10.1172/JCI87993.
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Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue

Abstract

In transplantation, there is a critical need for noninvasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor-specific exosomes into recipient circulation and that the quantitation and profiling of donor intra-exosomal cargoes may constitute a biomarker platform for monitoring rejection. Here, we have tested this hypothesis in a human-into-mouse xenogeneic islet transplant model and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, we quantified islet transplant exosomes in recipient blood over long-term follow-up using anti-HLA antibody, which was detectable only in xenoislet recipients of human islets. Transplant islet exosomes were purified using anti-HLA antibody–conjugated beads, and their cargoes contained the islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to a marked decrease in transplant islet exosome signal along with distinct changes in exosomal microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet and renal transplantation, donor exosomes with respective tissue specificity for islet β cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up periods of up to 5 years. Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a noninvasive window into the conditional state of transplant tissue.

Authors

Prashanth Vallabhajosyula, Laxminarayana Korutla, Andreas Habertheuer, Ming Yu, Susan Rostami, Chao-Xing Yuan, Sanjana Reddy, Chengyang Liu, Varun Korutla, Brigitte Koeberlein, Jennifer Trofe-Clark, Michael R. Rickels, Ali Naji

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Figure 6

Quantitation of transplant islet exosome signal in human allogeneic islet transplantation over long-term follow-up.

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Quantitation of transplant islet exosome signal in human allogeneic isle...
(A–D) Plasma samples from islet transplant recipients, patients A–D, were analyzed on NanoSight using anti-donor HLA class I–specific antibody quantum dot, and the transplant islet exosome signal (primary y axis, blue line) was quantified over long-term follow-up (up to 1,848 days after transplant). In all 4 patients, the pretransplant sample showed donor HLA exosome signal equivalent to the IgG isotype, but all the post-transplant samples reliably showed long-term tracking of the donor-specific HLA exosome signal (P = 0.0001). Recipient plasma [C-peptide (ng/ml) to glucose (mg/dl) ratio] × 100 values over the follow-up period are also shown (secondary y axis, black line). (E) Mean transplant islet exosome signal in patients B–D is shown along with the signal in patient A separately, as the latter subsequently developed diabetes. Unlike patients B–D, who maintained TISE signal greater than 0.35 at all post-transplant time points, patient A showed progressive loss in TISE signal to below 0.35 by the day 1,001 time point, when the plasma C-peptide–to–glucose ratio was still normal. However, at the day 1,001 time point, patient A developed signs of recurrent autoimmunity as evidenced by rapid increase in the β cell autoimmune antibody GAD65 (secondary y axis). This patient subsequently developed hyperglycemia requiring exogenous insulin therapy by the day 1,198 time point (Supplemental Table 2).